Episodic falling syndrome (EFS) is a unique genetic disorder in the cavalier King Charles
spaniel. It has been recognized in the breed since the 1960s. No other breed is
known to suffer from it.

EFS is a non-progressive disorder that tends to improve with therapy, and the
life spans of affected dogs do not appear to be shortened by the disease.

Veterinarians may refer to it as hyperexplexia or
muscle hypertonicity (and medically known as "paroxysmal exercise-induced
dystonia or dyskinesia"). However, recent research (November 2010, July 2011,
and January 2012) has established that EFS is
not a muscular condition, but is due to a single recessive gene associated with
brain function, a mutation of the BCAN gene. As a result, affected puppies are
more likely to be found in cases of line breeding or inbreeding on carrier
bloodlines.

Until 2010, EFS appeared to be a life-long condition of the cavaliers affected by
it. However, research that year found that milder cases of EFS are more of a
common condition in the CKCS, which tend to stabilize by age one year. EFS rarely is life-threatening.
A July 2011 UK/US study found that, "carriers are
extremely common (12.9%)." In a May 2012
report of DNA testing of 2,811 cavaliers, only 3.7% were affected with EFS,
but another 21.52% were carriers of the EFS gene, which is nearly double the
percentage predicted in the July 2011 study.

In a
June 2012 report of DNA testing of 280 cavaliers, the UK's Animal Health
Trust researchers estimate that 19.1% of CKCSs are carriers of EFS, 35% of
wholecolors (rubies and black-and-tans) are carriers, 0.3% of particolors (Blenheims
and tri-colors) are affected with EFS, and 5.1% of wholecolors are affected.

Some researchers have suggested that EFS in cavaliers may be associated with
another disorder unique to the breed, called "idiopathic asymptomatic
thrombocytopenia", an abnormally low number of blood platelets.
Drs. Jens Häggström and Clarence Kvart of Sweden have
noted in a 1997 article that thromboembolic events in
the cerebral circulation of blood may be involved in EFS. See
Blood Platelets for more information.

Symptoms of EFS vary, but they all are attributed to the dog’s muscles being
unable to relax. Typical signs include the cavalier engaged in exercise or being
excited or stressed, and then suddenly develop a rigid gait in
the rear limbs,
extending and retracting in an exaggerated, stiff manner, like that of a hopping
rabbit. The dog’s back may be arched, and the dog often yelps. One or more limbs
may also protract excessively. (See the photo at left of a ruby cavalier in
the throes of arched protraction.) The dog may lose its footing while running. It
usually loses all coordination and collapses on its side or on its face. When
the cavalier collapses, it may hold its forelegs over its head. In some
instances, the cavalier’s symptoms follow a “deer-stalking” behavior, with its
head held close to the ground and its rear high in the air, as if stalking game.
In the most severe cases, the dog may hold its head so low that its hind
quarters somersault over its head. The affected cavalier may exhibit these
symptoms only when excited or stressed, but in some cases, the behaviors have
not been stress-induced. The dog may also overheat during an episode,
possibly due to an inability to pant.

The cavalier does not lose consciousness during the episodes, and mentally,
it remains normal. Technically, the collapse is not a seizure, although it may
be appear as one. The CKCS appears to know what is happening to it, and sees
clearly, but loses control of its body. Afterwards, in most instances the dog
recovers relatively quickly; it stands up and acts as if nothing unusual had
occurred. However, if the cavalier exercises again immediately after recovery,
it may induce another episode.

Also, some severely affected cavaliers have been known to lapse into
repeated, lengthy episodes of the syndrome, and may even suffer permanent
neurological injuries and not be able to recover from the attacks. At least a
few CKCSs are known to have been euthanized to avoid continued suffering from
the disorder.

It is to be distinguished from presyncope, another disorder to
which cavalier King Charles spaniels are predisposed, which has some of the same
symptoms. Syncope in cavaliers is associated with late stages of mitral valve
disease. For more information on syncope and presyncope in CKCSs, see
Mitral Valve
Disease and Syncope.

Episodic falling syndrome is the result of a single recessive gene mutation
associated with neurological function. Until 2010, EFS had been believed to be a type of metabolic muscle disorder.
The ages of cavaliers studied with EFS have varied from two months to four
years. Both male and female CKCSs are affected. (The CKCS at right
experiencing EFS is a ten-month-old. Courtesy, Dr. Boaz Levitin.)

The dogs are neurologically normal between episodes. Electromyographic
evaluation detects the muscles at rest and engaged in no abnormal spontaneous
activity. There is no evidence of heart or respiratory problems during the
episode or the collapse. Blood tests, spinal fluid analysis, muscle biopsies,
and magnetic resonance imaging (MRI) of the brain have not proved to be helpful
in diagnosing the syndrome. Diagnosis, therefore, has been based solely upon the
symptoms of the episode.

Since some of the symptoms of EFS are similar to other disorders, such as
liver shunt, an epileptic seizure, or syringomyelia, the examining veterinarian
may mis-diagnose the episodes and unnecessarily screen the dog for those other
maladies. The primary differences between EFS and other disorders are that they
usually are induced by exercise, excitement, stress, or apprehension; the
EFS-affected dog remains conscious during the episodes; and the dog rarely will
experience any continuing pain or discomfort.

Therefore, video recordings of the dog’s EFS episodes are helpful to the
veterinarian in diagnosing the disorder. If a video device is not available, the
owner should write a precise report of the Cavalier’s behaviors during the
episode, to avoid mis-diagnosis, needless testing, and treatment with drugs
which may inadvertently aggravate the condition.

In a brief
July 2009 article, UK researchers Dr. Richard J Piercy and Gemma
Walmsley disclosed that they had identified a genetic form of muscular
dystrophy in the cavalier, with symptoms (weakness and exercise intolerance)
similar to some of those of EFS. However, these other symptoms of this
muscular dystrophy may clearly distinguish it from EFS: muscle atrophy,
difficulty swallowing, and an enlarged tongue. Also, the researchers have
found that only males are affected by this form of muscular dystrophy, and the
females are only carriers of the mutation.

In 2011, two UK research groups (see below) independently developed DNA swab
tests for detecting a recessive gene associated with brain function, the BCAN
gene, which, when mutated, is the cause of episodic falling disorder in the
CKCS. EFS is inherited as a autosomal recessive trait. If a DNA-tested cavalier is found to not have the mutated BCAN
gene, then it is "clear" of EFS. If the dog is found to have two of the mutated
gene, then it is "affected" and has EFS, whether it shows symptoms or not. If
the dog is found to have only one of the mutated gene, then it is not affected
but is "a carrier".*

* Despite the
studies distinguishing dogs with a pair of the mutated genes as
"affected" and dogs with only one of those genes as "carrier", there
have been clinical reports that some carriers display symptoms of EFS.

The knowledge of whether a cavalier is clear, affected, or a carrier of EFS
is important to the responsible breeder who wants to avoid passing EFS to future
generations in her bloodline of cavaliers. See
Breeders' Responsibilities below for
additional information about how to use the results of DNA testing to choose
breeding partners.

•LABOKLIN: Researchers led by Dr. Robert Harvey
of the London School of Pharmacy, Dr. Leigh Anne Clark
(Clemson) and Dr. Diane Shelton (Univ. Cal. at San Diego)
(email gshelton@ucsd.edu) have identified the underlying genetic defect
causing EFS in cavaliers. They found:

"Consistent with the unique clinical observed in affected
dogs, we discovered that a homozygous microdeletion affecting BCAN is associated
with EFS in CKCS dogs, confirming that this disorder is inherited in an
autosomal recessive manner. This mutation was not detected in
control DNA samples from 54 other dog breeds, confirming the unique nature of
this genomic rearrangement. ... Wider testing of a
larger population of CKCS dogs without a history of EFS from the USA revealed
that carriers are extremely common (12.9%). The development of
molecular genetic tests for the EFS microdeletion will allow the implementation
of directed breeding programs aimed at minimizing the number of animals with EFS
and enable confirmatory diagnosis and pharmacotherapy of affected dogs."

See report here for details. LABOKLIN's website
for ordering the test kit is
here.

•PawPrint Genetics:
Paw Print Genetics, a US company located in Spokane, Washington, offers
test kits for identifying the genetic defect causing EFS in cavaliers.
Pat Print Genetics' website for ordering the test kit is
here.

The Animal Health Trust (AHT) reported that, as of May
15, 2012: 2,811 cavaliers had been DNA-tested for episodic falling syndrome,
of which 104 (3.7%) were "affected" with two of the mutated EFS gene; 605
(21.52%) were "carriers" with only one of the mutated gene; and the rest, 2,102
(74.78%), were clear of the defective gene.

In a
June 2012 report of DNA testing of 280 cavaliers, AHT researchers estimate
that 19.1% of CKCSs are carriers of EFS, 35% of wholecolors (rubies and
black-and-tans) are carriers, 0.3% of particolors (Blenheims and tri-colors) are
affected with EFS, and 5.1% of wholecolors are affected.

During
and after an episode, consider trying to comfort the dog by holding it gently.
Do not force the dog's legs to assume any position. Keep the dog as cool as
possible, and allow it to rest as much as it wishes after the episode.

Until
recently, no medications appeared to remedy the condition, and there was no
known effective treatment. Affected dogs have not been found to respond to
anticholinesterases. Phenobarbital (Epiphen, Solfoton), a barbiturate, frequently is
prescribed.

In a study concluded in 2002, a
group of affected cavaliers was treated with another benzodiazepine drug,
clonazepam (Klonopin, Rivotril), which is a drug used to treat humans for
hereditary hyperexplexia or hyperekplexia ("startle disease"). Both diazepam and
clonazepam enhance gamma-aminobutyric acid (GABA) neurotransmission. However, clonazepam is more potent
than diazepam in equivalent doses, and clonazepam has more anti-convulsant
effects. In the 2002 study, with clonazepam treatment (at 0.5 mg/kg tid), the
episodes decreased in frequency from between 25 and 30 per week to as few as one
every two to three months. After two years of treatment with clonazepam, dogs in
the study were described as clinically normal. It has been
reported that CKCSs tend to be less responsive
to diazepam than other breeds, but that cavaliers can markedly improve with clonazepam.

Dr. Jacques Penderis(at right)
(formerly a senior research neurologist at the Animal Health Trust in the UK and
now at the University of Glasgow) has found that although some cavaliers
initially respond well to treatment with clonazepam or diazepam, the dogs tend
to develop tolerance to the drugs after a while and the beneficial effect wears
off. Dr. Penderis states that the current treatment options for CKCSs with
episodic falling syndrome are extremely limited.

In cases that do not respond to clonazepam and where the episodes are not
particularly severe or frequent, it may be best to accept the collapse episodes
and try to identify and avoid events or stressors that may trigger the episodes.
In severe cases, treatment can be tried with acetazolamide (Diamox), which is a
carbonic anhydrase inhibitor which has shown some efficacy in autosomal dominant
hyperkalemic periodic paralysis. Use of acetazolamide must only be done under
careful veterinary supervision, and a number of dogs do not appear to tolerate
the drug very well.

In a
January 2017 review of involuntary movements in dogs -- paroxysmal
dyskinesias -- the authors stated:

"In dogs, successful treatment of PNKD [paroxysmal
nonkinesigenic dyskinesia] has been reported, albeit
uncommonly, with clonazepam, acetazolamide and fluoxetine. Acetazolamide
was also very effective in the management of EFS in Cavalier King
Charles spaniels."

In a
2015 abstract, French researchers report that Fluoxetine,
a selective serotonin reuptake inhibitor, was successful in treating two
cavaliers with EFS and three Scottish terriers with Scotty cramp,
resulting in early and long term remission of the symptoms.

-- Vitamin E, tryptophan

Vitamin E and tryptophan
reportedly may decrease the frequency and severity of episodes. However,
tryptophan (tryptophan hydroxylase 1) can increase serotonin levels, and a high level of serotonin is a
suspected cause of early-onset mitral valve disease in the CKCS.

-- Chiropractic

Periodic chiropractic treatments may be able to minimize an affected dog's
symptoms of EFS.

-- breeding decisions using DNA results

• If two clear cavaliers are
mated, all offspring likewise should be clear of EFS.

• If a clear cavalier is mated to a
carrier, each puppy has an equal (50%) chance of being clear or carrier.
However, the outcome for each puppy is independent of all the other puppies so
in any particular litter one might not necessarily get half clears and half
carriers.

• If two carriers are mated, each puppy
has a 50% chance of being a carrier, and a 25% chance of being either affected
or clear, the outcome for each puppy being independent of all the other puppies.

• If a carrier and an affected are mated,
each puppy has an equal (50%) chance of being affected or carrier, the outcome
for each puppy being independent of all the other puppies.

• If two affecteds are mated,
all puppies in the litter should be affected.

Obviously, it would be preferable to mate only clear cavaliers to each other.
But if a cavalier breeder finds that one of her breeding stock is a carrier, she
should mate that dog only to a clear cavalier. Then, once the litter is
produced, the breeder should DNA-test the puppies to identify which ones are
clear and which are carriers, and remove the carriers from the breeding
program.*

"In dogs, successful treatment of PNKD [paroxysmal
nonkinesigenic dyskinesia] has been reported, albeit
uncommonly, with clonazepam, acetazolamide and fluoxetine. Acetazolamide
was also very effective in the management of EFS in Cavalier King
Charles spaniels."

"In dogs, the first genetically mapped PD [paroxysmal dyskinesia] was
that associated with EFS [episodic falling syndrome] in Cavalier
King Charles Spaniels (Forman et
al., 2012;
Gill et al., 2012). The mutation was characterised as a deletion
affecting the brevican gene (BCAN) which encodes a brain-specific
component of the extracellular matrix proteoglycan complex. It is
thought to be involved in homeostasis and mutations of this protein
result in a disruption of axonal conduction and synaptic stability. An
interesting observation in EFS is that the condition is self-limiting in
some cases (Forman et al., 2012). It is
suggested that compensatory pathways involving up regulation of other
proteoglycans may occur and account for this rectification. Dogs in our
study also seemed to show this improvement with age so a similar
compensatory mechanism may be considered."

"Episodic falling in Cavalier King Charles Spaniels (CKCS), an
autosomal-recessive inherited disorder, shares similarities with human
paroxysmal dyskinesia. In affected dogs, exercise and excitement can
precipitate episodes of abnormal gait and fallings which last up to
several minutes. There are no signs of an impairment of consciousness or
autonomic dysfunction during or after these attacks. Affected animals
develop an increased extensor muscle tone of all four limbs, resulting
in an immobilized, 'deer-stalking'
or
'praying' position, sometimes
falling with legs held in extensor rigidity. Other clinical signs are
facial muscle stiffness, stumbling, a 'bunny-hopping' gait, and arching
of the back. It is unclear if cocontractions of flexors are involved.
Initial clinical signs of the disease typically appear between 3 and 7
months of age. Interestingly, in some cases, there is spontaneous
remission, as sometimes observed in human paroxysmal dyskinesia. There
is no evidence for metabolic alterations as a cause, and light
microscopic examinations have not revealed any lesions in the CNS or
peripheral nerves. Clonazepam may be effective in suppressing the
episodes in some cases. Recently, a 15.7 kb deletion in BCAN, encoding
the brain-specific extracellular matrix-proteoglycan brevican, was found
to be associated with episodic falling in CKCS. This protein plays an
important role in cell adhesion, migration, axon guidance, and neuronal
plasticity. How this mutation leads to the manifestation of this
hyperkinetic movement disorder in dogs has yet to be unraveled."

The article includes a one-minute MP4 video of a CKCS with EFS, which
is available here. (Photos above are from that video.)

April
2013:
UK's Kennel Club adopts the DNA testing scheme for episodic falling syndrome
in the CKCS. Finally, the UK Kennel Club has announced that it has
approved the DNA testng scheme for episodic falling syndrome (and also for curly
coat syndrome) in the cavalier breed. Details on the
KC's
website here.

March
2013:
UK cavalier clubs urge Kennel Club to include Episodic Falling DNA test in KC's
registration system. The UK cavalier clubs'
Cavalier Health Laison Committee voted to ask the UK Kennel Club to include
all results from the Episodic Falling (EF) and Curly Coat (DE/CC) DNA tests in
the KC’s registration system and in its Health Test Results Finder. Furthermore
the Clubs requested that all cavaliers be tested for both EF and DE/CC prior to
breeding and that at least one parent of each litter is free of each mutation,
to ensure no affected puppies can be produced or registered.

June
2012: UK's Animal Health
Trust estimates 19.1% of CKCSs are EFS carriers. The Animal Health
Trust has issued its report of its examination of DNA of 280 UK Kennel Club
cavalier King Charles spaniels. Based upon the results of the study, AHT has
estimated that 19.1% of the overall population of UK cavaliers are carriers of
episodic falling syndrome. The study also included the CKCSs' curly coat
syndrome. AHT estimates that 10.8% of cavaliers are carriers of curly-coat.

The EFS mutation was found nearly five times more frequently in wholecolors
(rubies and black and tans) than in the particolors (Blenheims and tri-colors).
The researchers concluded that19.1% of CKCSs are carriers of EFS, 35% of
wholecolors (rubies and black-and-tans) are carriers, 0.3% of particolors (Blenheims
and tri-colors) are affected with EFS, and 5.1% of wholecolors are affected.

May
2012: UK's Animal Health Trust reports interim results of DNA testing.
The Animal Health Trust reported that, as of May 15, 2012: 2,811 cavaliers have
been DNA-tested for episodic falling syndrome, of which 104 (3.7%) have been
found to be "affected" with two of the mutated EFS gene; 605 (21.52%) are
"carriers" with only one of the mutated gene; and the rest, 2,102 (74.78%), are
clear of the defective gene.

July
2011: UK's LABOKLIN offers genetic test for
Episodic Falling Syndrome. Researchers led by Dr. Robert Harvey
of the London School of Pharmacy, Dr. Leigh Anne Clark
(Clemson) and Dr. Diane Shelton (Univ.Cal. at San Diego) have identified the underlying genetic defect
causing EFS in cavaliers. They found:

"Consistent with the unique clinical observed in affected
dogs, we discovered that a homozygous microdeletion affecting BCAN is associated
with EFS in CKCS dogs, confirming that this disorder is inherited in an
autosomal recessive manner. This mutation was not detected in
control DNA samples from 54 other dog breeds, confirming the unique nature of
this genomic rearrangement. ... Wider testing of a
larger population of CKCS dogs without a history of EFS from the USA revealed
that carriers are extremely common (12.9%). The development of
molecular genetic tests for the EFS microdeletion will allow the implementation
of directed breeding programs aimed at minimizing the number of animals with EFS
and enable confirmatory diagnosis and pharmacotherapy of affected dogs."

April
2011: UK's Animal Health Trust
begins offering a DNA test for EFS. Starting on April 18, the Animal
Health Trust will offer to cavalier breeders a DNA swab test to detect the mutations
causing episodic falling syndrome in their cavalier breeding stock. Go to AHT’s
online DNA testing
webshop for more details. The DNA test is available world-wide.
Read more here.

February
2011: Dr. Penderis reports discovery
of single gene causing EFS. Dr. Jacques Penderis reported at the
2011 Veterinary Ireland Conference and in an interview with Irish journalist
Karlin Lillington that his reasearch team has identified a single recessive
gene mutation causing EFS. He said that a genetic test for the gene should be
released in the spring of 2011, probably in April.

November
2010:DNA Region for Episodic
Falling Syndrome Has Been Found. Animal Health Trust veterinary
geneticist Dr. Tom Lewis announced at the UK Cavalier Club's
"Cavalier Health Day" on November 20 that the DNA region for the episodic
falling syndrome in cavaliers has been located. The AHT is continuing its
research to identify the precise mutations of gene(s) causing EFS. The
Trust's future plan is to offer a DNA test for the mutations to cavalier
breeders.

April
2009: Dr. Penderis researches inheritance pattern of EFS in CKCSs.
Dr. Jacques Penderis
is conducting research to try to establish the pattern of inheritance of
episodic falling in the cavalier. He is collecting pedigrees from affected dogs
for pedigree analysis, particularly where the disease status of related dogs
(e.g. parents and litter mates) are known.

He reports that funding is now in place to perform a genome scan in the
cavalier to try and identify the genetic region of interest responsible for
episodic falling. Funding is still required for the fine sequencing to follow
the genome scan. Anyone interested in contributing to these projects should
contact Dr. Cathryn Mellersh at the Animal Health Trust, email:
Cathryn.Mellersh@ aht.org.uk

For this study Dr. Penderis is very interested in collecting blood samples or
cheek swabs for DNA extraction from affected dogs, and normal related dogs. Dr.
Penderis requires blood samples from known affected dogs and from as many normal
related dogs as possible (particularly litter mates, parents, grandparents and
offspring). The study's goal is to develop a genetic test to allow
identification of the affected dogs and asymptomatic carriers, so that the
disease may be totally eradicated from all tested breeding lines. Dr. Penderis
may be contacted at Clinical Neurology / Neurosurgery Service, Faculty of
Veterinary Medicine, University of Glasgow, Bearsden Road, Glasgow G61 1QH, Tel:
+(44) 0141 330 5738 (office), Email: j.penderis@vet.gla.ac.uk

October
2007: Animal Health Trust team is to research episodic falling in CKCSs. Dr.
Jacques Penderis reported that he has teamed up with Dr. Cathryn
Mellersh of the Animal Health Trust and a graduate student, Oliver Forman, to
conduct a study of four canine neurological conditions, including episodic
falling in the CKCS. Also, Professor Robert Harvey, of The School of Pharmacy in
London. has proposed some "interesting candidate genes" for the cavaliers they
we will be jointly studying.

These candidate gene studies are in need of financial underwriting. Dr.
Penderis estimates that it will cost £2,000 +/- for the candidate gene work, and
there will be the sequencing costs to follow that, in excess of £6,000. Anyone
interested in contributing to these projects should contact Dr. Cathryn Mellersh
at the Animal Health Trust, email: Cathryn.Mellersh@aht.org.uk

A myopathy associated with muscle hypertonicity in the
Cavalier King
Charles Spaniel. Wright JA, Smyth JBA, Brownlie S, Robins M. J Com Path
1987;97:559-565. Quote: "Clinical signs of electrically silent muscle
hypertonicity are described in five Cavalier King Charles dogs.
Biopsies of the biceps femoris and triceps muscles, when examined with the
electron miscroscope, revealed evidence of sarcotubular and mitochondrial
abnormalities. These included enlargement of the sarcoplasmic reticulum,
hydropic degeneration of mitochondria, tubular proliferations in the vicinity of
the triads and vacuolar invagination of mitochondria. The exact nature of these
findings is not clear and it is suggested that utilization of tracer techniques
would help to explain them."

Update on Mitral Valve Disease. Jens
Häggström and Clarence Kvart. Proc. 15th ACVIM Forum; 1997. Quote: "An
interesting observation that may be of comparative interest is that Cavalier
King Charles Spaniels have been shown to have a high prevalence (30%) of
thrombocytopenia and macrothrombocytosis. Humans with MVP [mitral valve prolapse]
tend to have shortened platelet survival times and thromboembolic episodes
primarily in the retinal and cerebral circulation. Thromboembolic events
in the retinal ore cerebral circulation may be involved in the disturbances
described in the breed as 'episodic falling' and 'fly catching'."

Hypertonicity in Cavalier King Charles Spaniels. Shelton GD,
Comparative Neuromuscular Lab, June 2001. Quote: "A syndrome of exercise-induced
muscle hypertonicity was described several years ago in young Cavalier
King Charles Spaniels (CKCS) from the UK. The history of exercise and
excitement-induced 'collapse' was preceded by a 'deer-stalking' action with the
head held close to the ground and the bottom high in the air. An increasingly
stilted gait was observed until there was finally collapse to one side. An
increase in extensor tone of the muscles of all four limbs was evident during
the period of collapse. The time period required for recovery of limb function
was usually about ten minutes. Mentation was not abnormal throughout the
episodes. Electromyographic evaluation showed the muscles were electrically
silent. While muscle biopsy specimens were not abnormal at the light microscopic
level, rather non-specific ultrastructural abnormalities were observed. A
similar syndrome has recently been identified in five CKCS dogs
from the USA (three males, two females). Two of the dogs were from Ohio and one
each were from Louisiana, Florida, and Illinois (See video clip). Age at
clinical presentation ranged from two-seven months. These dogs showed very
similar clinical presentations to the dogs originally described from the UK.
Where evaluated, neither electrophyiological or histological abnormalities were
identified. ... Clonazepam has been used in two affected CKCS
dogs with reports of approximately 70-80% improvement suggesting a problem with
GABA neurotransmission. Investigators at the Comparative Neuromuscular
Laboratory at the University of California, San Diego are interested in being
notified of any other possibly affected dogs."

Hypertonicity in Cavalier King Charles Spaniels. Garosi LS, Platt
SR, Shelton GD. J Vet Intern Med 2002; 16:330. Quote: "A syndrome of
exercise-induced muscle hypertonicity was described several years ago in young
Cavalier King Charles Spaniels (CKCS) of common ancestry from
the United Kingdom. Recently, 3 CKCS with very similar clinical
presentations were evaluated in the UK and 4 dogs were identified in the USA.
Age at presentation ranged from 4 to 7 months and both males and females were
affected. A typical history included exercise and excitement-induced 'collapse'
which was preceded by a 'deer-stalking' action with the head held close to the
ground and the bottom high in the air. An increase in extensor tone of the
muscles of all four limbs was evident prior to falling over and during the
period of collapse. Mentation was not abnormal throughout the episodes.
Hereditary hyperekplexia (also called startle disease), a syndrome described in
humans, has a similar clinical presentation in which hypertonia may be elicited
by unexpected auditory, visual, or sensory stimuli. Similar to the falling over
that occurs in the CKCS, these attacks in humans may result in
unchecked falling despite complete retention of consciousness. Hyperekplexia in
humans responds dramatically although not completely to the benzodiazepine drug
clonazepam, which enhances gamma-aminobutyric acid (GABA) neurotransmission. Low
levels of CSF GABA have been reported in human patients. Following extensive
neurological and neuromuscular evaluations that resulted in no specific
abnormalities, a treatment trial with oral clonazepam (0.5 mg/kg TID) was
performed in 2 affected CKCS dogs in the UK and 2 dogs in the
USA. All 4 dogs responded dramatically to clonazepam therapy. Episodes of
hypertonicity decreased from 25–30 per week to 1 every 2–3 months. after 2 years
of therapy with clonazepam, the 2 dogs from the USA were described as clinically
normal with only infrequent episodes. Although the inciting stimuli differ, the
response to clonazepam therapy suggests a similar underlying disorder of GABA
neurotransmission in the CKCS dogs and human hyperekplexia
patients."

Clinical Neurology in Small Animals - Localization, Diagnosis and
Treatment. K.G. Braund, International Veterinary Information Service,
Ithaca, New York, USA; Paroxysmal Disorders (6-Feb-2003). Quote: "Episodic
falling or hypertonicity is a well-recognized paroxysmal disorder in
Cavalier King Charles Spaniels in the UK, and has been seen in the
United States and Australia."
www.ivis.org/special_books/Braund/braund29/ivis.pdf

A rare syndrome in cavaliers. G.
Diane Shelton. AKC Gazette. Apr. 2003:24. Quote: "Dr. G. Diane Shelton, of the
University of California at San Diego, reported on the treatment of several
Cavalier King Charles Spaniels diagnosed with exercise- induced
muscle hypertonicity. This syndrome was described several years ago in dogs from
the United Kingdom, but seven cases that were identified recently included four
dogs in the United States. Male and female Cavalier pups with a
history of exercise- or excitement-induced collapse had been presented. They
were between 4 and 7 months of age at the time. Exactly when the symptoms began
is unclear. A typical event of this syndrome begins with activity that looks
like stalking: The dog holds its head to the ground with its hindquarters up in
the air. As the event progresses, the legs straighten and become tense, which
ultimately causes collapse. Mentally, the dog remains normal. It knows what is
happening and apparently sees clearly, but seems to lose control of its body.
After extensive tests that yielded no specific abnormalities, two of the U.S.
dogs and two of the U.K. dogs were treated with clonazepam, the drug commonly
used to treat people with a similar syndrome called hereditary hyperekplexia (or
startle disease) . With treatment, episodes decreased in frequency from between
25 and 30 each week down to one every two to three months. After two years of
clonazepam, the two U.S. dogs were described as clinically normal. Episodes were
infrequent."

A Practical Guide to
Canine and Feline Neurology. Curtis W. Dewey. John Wiley & Sons; 2008;
4-6, 482-483. Quotes: "Breed-associated neurologic abnormalities of dogs and
cats. ... Cavalier King Charles Spaniels ... Episodic muscle
hypertonicity ("falling cavaliers" -- probable dyskinesia" pg. 4-6. ""An age
range ... has been reported of ... 14 weeks to 4 years for Cavalier King
Charles Spaniels. ... Crossing of the thoracic limbs over the top of
the head has been described in collapsing Cavalier King Charles Spaniels.
... Cavalier King Charles Spaniels tend to be less responsive
to diaaepam than other breeds with the condition, but they can markedly improve
with clonazepam treatment. Tolerance to clonzepam may develop in the long term.
Other therapies reported to decrease frequency and severity of episodes include
vitamin E and tryptophan. This is a nonprogressive disorder that tends to
improve with therapy. Life spans of affected dogs do not appear to be shortened
by the disease." pp. 482-483.

Muscular
dystrophy in Cavalier King Charles spaniels. Piercy,
Richard. J. and Walmsley, Gemma. Vet Rec. 2009 165 (2), p. 62. Quote: "We have
recently identified the genetic cause of a form of muscular dystrophy in
CKCS. The causative mutation is in the dystrophin gene and the X-linked
disease is associated with weakness, muscle atrophy and exercise intolerance,
detectable from a few months of age. Prominent signs in affected dogs are
dysphagia [the symptom of difficulty in swallowing] and macroglossia (enlarged
tongue)[tongue enlargement that leads to functional and cosmetic problems].
Serum creatine kinase is usually markedly elevated. Male dogs with the mutation
[are] clinically affected and female dogs with the mutation are silent carriers.
We are also keen to hear from veterinary surgeons who believe they may have seen
an affected dog in their practice, in order to estimate the prevalence of this
disease and limit its spread by genetic testing." Contact Dr. Piercy at
the Royal Veterinary College's Comparative Neuromuscular Diseases Laboratory at
rpiercy@rvc.ac.uk

Update: Mutation Identified in Episodic Falling Syndrome in Cavalier
King Charles Spaniel Dogs. Dr. Diane Shelton.
Comparative Neuromuscular Lab,
March 2011. Quote: "Almost 30 years ago a syndrome of exercise-induced muscle
hypertonicity and falling (Episodic Falling, EFS) was described in young
Cavalier King Charles Spaniels (1-3, and June 2001 Case of the Month).
Clinical signs included exercise and excitement-induced “collapse” that was
preceded by a “deer-stalking” action with the head held close to the ground and
the bottom high in the air. An increasingly stilted gait was observed until
there was finally collapse to one side. An increase in extensor tone in the
muscles of both the thoracic and pelvic limbs was present during the period of
collapse. The time period required for recovery of limb function was usually
about 10 minutes. Mentation was normal throughout the episodes.
Electromyographic evaluation showed the muscles were electrically silent. Dogs
were neurologically normal between episodes. A microdeletion in the central
nervous system gene BCAN1 has been shown to be highly associated with EFS in
CKCS dogs and a scientific paper recently published (4). The
carrier rate was approximately 13% suggesting that the EFS microdeletion is
present at a high frequency in the general CKCS population.
Molecular genetic testing for the EFS microdeletion is now available through
Laboklin. Information regarding testing can be found
here."

Genetic Connection: A Guide to Health Problems in Purebred Dogs, Second Edition. Lowell Ackerman. July 2011; AAHA Press; pg
120. Quote: "Episodic falling is an autosomal recessive disorder of muscle
innervation reported in the Cavalier King Charles spaniel. It is often
detected in affected animals in their first year of life, when they are unable
to relax, their muscles become rigid and they fall over. Typical triggers are
exercise, excitementt, or frustration. Fortunately, DNA testing is available to
detect clear, carrier, and affected animals."

New DNA tests for
Cavalier King Charles spaniels. Vet Rec 2011 168(14):370. "NEW DNA
tests to detect the mutations causing congenital keratoconjunctivitis sicca and
ichthyosiform dermatosis (dry eye and curly coat syndrome) and episodic falling
in Cavalier King Charles spaniels will be available from the
Animal Health Trust (AHT) later this month. Episodic falling is a neurological
condition induced by exercise, excitement or frustration. The dog's muscle tone
increases and the animal is unable to relax its muscles, becomes rigid and falls
over. Dry eye and curly coat syndrome results in an affected dog producing no
tears, so its eyes become sore. The skin becomes flaky and dry, particularly
around the feet, which can make standing and walking difficult and painful. The
syndrome appears to be unique to Cavalier King Charles spaniels
and most dogs diagnosed with it are euthanased. Researchers at the Kennel
Club Genetics Centre at the AHT have now identified the mutations responsible
for the two conditions. This has allowed the development of the new DNA tests,
which will be available from the AHT from April 18. Cathryn Mellersh, head of
canine genetics at the AHT, said: To date there has been no long-term effective
treatment for either dry eye and curly coat syndrome or episodic falling
so the development of the DNA tests is an important breakthrough for breeders
and owners of Cavalier King Charles spaniels. As with all
inherited disease, it's important that breeders are armed with the facts
and that they still continue to use carrier dogs in their breeding programmes.
Breeding a carrier with a non-carrier will not produce affected puppies;
however, breeding just clear dogs with other clear dogs could reduce the
gene pool within the breed and this could lead to other health problems in the
future."

A canine BCAN microdeletion associated with Episodic
Falling Syndrome. Jennifer L. Gill, Kate L. Tsai, Christa Krey, Rooksana E.
Noorai, Jean-François Vanbellinghen, Laurent S. Garosi, G. Diane Shelton, Leigh
Anne Clark, and Robert J. Harvey. Neurobiology of Disease. Jan
2012;45(1):130-136. Quote:
"Episodic falling syndrome (EFS) is a canine paroxysmal hypertonicity disorder
found in Cavalier King Charles spaniels. Episodes are triggered
by exercise, stress or excitement and characterized by progressive hypertonicity
throughout the thoracic and pelvic limbs, resulting in a characteristic
'deer-stalking' position and/or collapse. We used a genome-wide association
strategy to map the EFS locus to a 3.48 Mb critical interval on canine
chromosome 7. By prioritizing candidate genes on the basis of biological
plausibility, we found that a 15.7 kb deletion in BCAN, encoding the
brain-specific extracellular matrix proteoglycan brevican, is associated with
EFS. This represents a compelling causal mutation for EFS, since brevican has an
essential role in the formation of perineuronal nets governing synapse stability
and nerve conduction velocity. ... Consistent with the unique clinical signs
observed in affected dogs, we discovered that a homozygous microdeletion
affecting BCAN is associated with EFS in CKCS dogs, confirming
that this disorder is inherited in an autosomal recessive manner. This mutation
was not detected in control DNA samples from 54 other dog breeds, confirming the
unique nature of this genomic rearrangement. ... Certainly, since EFS appears to
result from a central nervous system rather than a muscle defect, the associated
sarcoplasmic reticulum pathology is likely to be a secondary manifestation of
muscle overstimulation. ... Mapping of the deletion breakpoint enabled the
development of Multiplex PCR and Multiplex Ligation-dependent Probe
Amplification (MLPA) genotyping tests that can accurately distinguish normal,
carrier and affected animals. Wider testing of a larger population of
CKCS dogs without a history of EFS from the USA revealed that carriers
are extremely common (12.9%). The development of molecular genetic tests for the
EFS microdeletion will allow the implementation of directed breeding programs
aimed at minimizing the number of animals with EFS and enable confirmatory
diagnosis and pharmacotherapy of affected dogs."

Parallel Mapping and
Simultaneous Sequencing Reveals Deletions in BCAN and FAM83H Associated with
Discrete Inherited Disorders in a Domestic Dog Breed. Oliver P. Forman,
Jacques Penderis, Claudia Hartley, Louisa J. Hayward, Sally L. Ricketts, and
Cathryn S. Mellersh.
PLoS Genet. 2012 January; 8(1): e1002462. Quote: "The domestic dog (Canis
familiaris) segregates more naturally-occurring diseases and phenotypic
variation than any other species and has become established as an unparalled
model with which to study the genetics of inherited traits. We used a
genome-wide association study (GWAS) and targeted resequencing of DNA from just
five dogs to simultaneously map and identify mutations for two distinct
inherited disorders that both affect a single breed, the Cavalier King
Charles Spaniel. We investigated episodic falling (EF), a paroxysmal
exertion-induced dyskinesia, alongside the phenotypically distinct condition
congenital keratoconjunctivitis sicca and ichthyosiform dermatosis (CKCSID),
commonly known as dry eye curly coat syndrome. EF is characterised by episodes
of exercise-induced muscular hypertonicity and abnormal posturing, usually
occurring after exercise or periods of excitement. CKCSID is a congenital
disorder that manifests as a rough coat present at birth, with
keratoconjunctivitis sicca apparent on eyelid opening at 10–14 days, followed by
hyperkeratinisation of footpads and distortion of nails that develops over the
next few months. We undertook a GWAS with 31 EF cases, 23 CKCSID cases, and a
common set of 38 controls and identified statistically associated signals for EF
and CKCSID on chromosome 7 (Praw 1.9×10-14; Pgenome=1.0×10-5) and chromosome 13
(Praw 1.2×10-17; Pgenome=1.0×10-5), respectively. We resequenced both the EF and
CKCSID disease-associated regions in just five dogs and identified a 15,724 bp
deletion spanning three exons of BCAN associated with EF and a single base-pair exonic deletion in
FAM83H associated with CKCSID. Neither BCAN or FAM83H have
been associated with equivalent disease phenotypes in any other species, thus
demonstrating the ability to use the domestic dog to study the genetic basis of
more than one disease simultaneously in a single breed and to identify multiple
novel candidate genes in parallel."

Canine Paroxysmal Movement Disorders. Ganokon Urkasemsin,
Natasha J. Olby. Vet. Clinics of No. Amer.: Small Animal Pract. Nov.
2014;44(6):1091-1102. Quote: "Paroxysmal dyskinesias are episodic movement
disorders characterized by muscle hypertonicity that can produce involuntary
movements. Signs emanate from the central nervous system; consciousness is
not impaired, ictal electroencephalography is normal, and there are no
autonomic signs, distinguishing them from seizure disorders. In humans they
are classified into 3 groups, each responding to different therapies. A
mutation in the gene for brevican (BCAN) has been identified as the cause of
Episodic Falling in Cavalier King Charles spaniels. Further
elucidation of the genetic causes will enhance our ability to identify and
treat these canine diseases."

Dystonia and Paroxysmal Dyskinesias: Under-Recognized Movement Disorders in
Domestic Animals? A Comparison with Human Dystonia/Paroxysmal Dyskinesias.
Angelika Richter, Melanie Hamann, Jörg Wissel, Holger A. Volk. Frontiers in
Vet. Sci. November 2015. Quote: "Generalized Movement Disorders Which
Possibly Include Dystonic Features -- Paroxysmal Dyskinesias in Dogs --
Episodic falling in Cavalier King Charles Spaniels (CKCS),
an autosomal-recessive inherited disorder, shares similarities with human
paroxysmal dyskinesia. In affected dogs, exercise and excitement can
precipitate episodes of abnormal gait and fallings which last up to several
minutes. There are no signs of an impairment of consciousness or autonomic
dysfunction during or after these attacks. Affected animals develop an
increased extensor muscle tone of all four limbs, resulting in an
immobilized, “deer-stalking” or “praying” position, sometimes falling with
legs held in extensor rigidity. Other clinical signs are facial muscle
stiffness, stumbling, a 'bunny-hopping' gait, and arching of the back. It is
unclear if cocontractions of flexors are involved. Initial clinical signs of
the disease typically appear between 3 and 7 months of age. Interestingly,
in some cases, there is spontaneous remission, as sometimes observed in
human paroxysmal dyskinesia. There is no evidence for metabolic alterations
as a cause, and light microscopic examinations have not revealed any lesions
in the CNS or peripheral nerves. Clonazepam may be effective in suppressing
the episodes in some cases. Recently, a 15.7 kb deletion in BCAN, encoding
the brain-specific extracellular matrix-proteoglycan brevican, was found to
be associated with episodic falling in CKCS. This protein
plays an important role in cell adhesion, migration, axon guidance, and
neuronal plasticity. How this mutation leads to the manifestation of this
hyperkinetic movement disorder in dogs has yet to be unraveled."

Long-term treatment of canine paroxysmal dyskinesias with fluoxetine: 6 cases.
T. Bouzouraa, C. Escriou. ESVN Abstract J. Vet. Int. Med. December 2015.
Quote: "It is only recently that both clinical features and genetic basis of
canine paroxysmal dyskinesias (CPDs) have been documented. Their management
remains challenging though phenothiazine, benzodiazepines even
anticonvulsants yielded unsatisfactory results. Fluoxetine, a selective
serotonin reuptake inhibitor, seems promising. Three Scottish terriers
(STs), 2 Cavalier King Charles Spaniels (CKCSs) suffering
from Scottie Cramp (SC) and Episodic Falling, respectively, then an English
Setter with a dyskinesia of unknown origin, displayed many daily episodes,
triggered by exercise and/or excitement that definitely preventing them from
living normally. All dogs received fluoxetine as a single treatment (2–4
mg/kg q24 h). Four dogs displayed early and complete remissions that
persisted over long periods (1 year for 1 CKCS then 2, 6 and 7 years for the
3 STs). The remaining 2 cases showed a significant improvement with a
decline to approximately one single episode every 2 months for both dogs.
Transient relapses occurred when treatment was interrupted or tapered in 3
dogs. No treatment resistance or side effect was observed. Fluoxetine may be
a good and safe option for the long-term management of CPDs, allowing dogs
for resuming to normal activity and lifestyle. It can directly correct
serotoninergic transmission imbalance suspected in SC. Its activity remains
unclear in other CPDs; direct serotoninergic action is likely but indirect
effect through a reduction of behavioral reactivity to triggering factors
like stress, excitation or environmental stimulations is also plausible."

Natural history of canine paroxysmal movement disorders in Labrador
retrievers and Jack Russell terriers. Mark Lowrie, Laurent Garosi.
Vet. J. July 2016;213:33-37. Quote: In dogs, the first genetically mapped PD
[paroxysmal dyskinesia] was that associated with EFS [episodic falling
syndrome] in Cavalier King Charles Spaniels (Forman
et al., 2012;
Gill et al., 2012). The mutation was characterised as a deletion
affecting the brevican gene (BCAN) which encodes a brain-specific component
of the extracellular matrix proteoglycan complex. It is thought to be
involved in homeostasis and mutations of this protein result in a disruption
of axonal conduction and synaptic stability. An interesting observation in
EFS is that the condition is self-limiting in some cases (Forman
et al., 2012). It is suggested that compensatory pathways involving up
regulation of other proteoglycans may occur and account for this
rectification. Dogs in our study also seemed to show this improvement with
age so a similar compensatory mechanism may be considered.

Frequency estimation of disease-causing mutations in the Belgian population
of some dog breeds - Part 2: retrievers and other breed types. E.
Beckers, M. Van Poucke, L. Ronsyn, L. Peelman. Vlaams Diergeneeskundiig
Tijdschrift. October 2016:185-196. Quote: A Belgian population of ten breeds
with a low to moderately low genetic diversity or which are relatively
popular in Belgium, i.e. Bichon frise, Bloodhound, Bouvier des Flandres,
Boxer, Cavalier King Charles spaniel, Irish setter,
Papillon, Rottweiler, Golden retriever and Labrador retriever, was genotyped
for all potentially relevant disease-causing variants known at the start of
the study. In this way, the frequency was estimated for 26 variants in order
to improve breeding advice. Disorders with a frequency high enough to
recommend routine genotyping in breeding programs are (1) degenerative
myelopathy for the Bloodhound, (2) arrhythmogenic right ventricular
cardiomyopathy and degenerative myelopathy for Boxers, (3) episodic falling
syndrome and macrothrombocytopenia for the Cavalier King Charles
spaniel, (4) progressive retinal atrophy rod cone dysplasia 4 for
the Irish setter (5) Golden retriever progressive retinal atrophy 1 for the
Golden retriever and (6) exercise induced collapse and progressive rod-cone
degeneration for the Labrador retriever. To the authors’ knowledge, in this
study, the presence of a causal mutation for a short tail in the Bouvier des
Flandres is described for the first time. ... The autosomal recessive
disorder episodic falling syndrome (EFS) causes neurological episodes often
triggered by stress, excitement or exercise. Symptoms occur at the age of
three months to four years and become progressively worse. A frequency of
12.3% (Wt/Mt) carriers was found in 57 genotyped animals, which is very
similar to the estimate of 12.9% carriers in a USA population (Gill
et al., 2011). No homozygous mutant individuals were encountered (Table
3). The authors encourage routine genotyping in breeding dogs because of the
high frequency.

Classification of involuntary movements in dogs: Paroxysmal dyskinesias.
Mark Lowrie, Laurent Garosi. Vet. J. January 2017. Quote: Paroxysmal
dyskinesias (PDs) are a group of hyperkinetic movement disorders
characterised by circumscribed episodes of disturbed movement, superimposed
on a background state in which such abnormality is absent. There is no loss
of consciousness. Episodes can last seconds, minutes or hours, and the
beginning and end of the movement disturbance is abrupt. Neurological
examination is typically normal between episodes. PDs are associated with a
broad spectrum of clinical presentations, encompassing various aetiologies.
... This review aims to synthesise a classification scheme for veterinary
PDs by reviewing human systems and applying them to veterinary examples.
However, it is anticipated that genetic advancement will greatly aid in
future stratification and therapy for PDs in dogs. Therefore, classification
systems should be viewed as works in progress that should be modified as
necessary. ... However, biochemical and genetic markers are available for
some PDs in dogs (notably canine epileptoid cramping syndrome [CECS] and
episodic falling syndrome [EFS] of the Cavalier King Charles spaniel,
respectively) and these have only served to confirm the suspicion of PD over
epilepsy in these breeds. ... Certain breed-specific features can aid in
achieving a definitive diagnosis. The work up for EFS in Cavalier
King Charles spaniels, for example, involves genetic testing,
whereas CECS in the Border terrier requires serological testing for
gluten-specific antibodies. ... The first genetically mapped PD in companion
animals was EFS in Cavalier King Charles Spaniels. ...
Medications: Medications used in the management of PD have variable and
often limited efficacy. In humans, carbamazepine is the drug of choice for
kinesigenic dyskinesias and clonazepam for the non-kinesigenic forms. A
major difference between PNKD and PKD in humans is that PNKD is relatively
refractory to therapy. In dogs, successful treatment of PNKD has been
reported, albeit uncommonly, with clonazepam, acetazolamide and fluoxetine.
Acetazolamide was also very effective in the management of EFS in
Cavalier King Charles spaniels. ... Highlights: • Paroxysmal
dyskinesias are circumscribed episodes of disturbed movement without loss of
consciousness. • Diagnosis is challenging; hence accurate identification is
critical. • Three forms of paroxysmal dyskinesia exist: kinesigenic,
nonkinesigenic and exertion-induced dyskinesia. • Paroxysmal dyskinesias are
typically self-limiting and have a benign course.

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